Perinatal asphyxia leads to acute kidney damage and increased renal susceptibility in adulthood.

Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging, and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 min) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), hypoxic and heat shock factors (hypoxia-inducible factor-1α, heat shock factor-1, and heat shock protein-27), proinflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and fibrotic markers (transforming growth factor-ß, connective tissue growth factor, and fibronectin) promptly after PA. Moreover, a machine learning model was identified through random forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic, heat shock, proinflammatory, and profibrotic response after renal IR injury compared with controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. In addition, the parameters identified through random forest analysis provide a robust foundation for future biomarker research in the context of PA.NEW & NOTEWORTHY This article demonstrates that perinatal asphyxia leads to subclinical kidney injury that permanently increases renal susceptibility to subsequent ischemic injury. We identified major molecular pathways involved in perinatal asphyxia-induced renal complications, highlighting potential targets of therapeutic approaches. In addition, random forest analysis revealed a model that classifies perinatal asphyxia with 95.5% accuracy that may provide a strong foundation for further biomarker research. These findings underscore the importance of multiorgan follow-up for perinatal asphyxia-affected patients.

Placental Histologic Abnormalities and 2-Year Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: We aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelopmental impairment (NDI) at 2 years of age after undergoing therapeutic hypothermia compared to subjects without acute placental changes. STUDY DESIGN: Among 500 subjects born at ≥36 weeks gestation with moderate or severe HIE enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, a placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute only, chronic only, or both acute and chronic histologic abnormalities. We calculated adjusted relative risks (aRRs) for associations between placental pathologic abnormalities and death or NDI at age 2 years, adjusting for HIE severity, treatment assignment, and site. RESULT: 321/500 subjects (64%) had available placental pathology reports. Placental abnormalities were characterized as acute only (20%), chronic only (21%), both acute and chronic (43%), and none (15%). The risk of death or NDI was not statistically different between subjects with and without an acute placental abnormality (46 vs. 53%, aRR 1.1, 95% confidence interval (CI): 0.9, 1.4). Subjects with two or more chronic lesions were more likely to have an adverse outcome than subjects with no chronic abnormalities, though this did not reach statistical significance (55 vs. 45%, aRR 1.24, 95% CI: 0.99, 1.56). CONCLUSION: Placental pathologic findings were not independently associated with risk of death or NDI in subjects with HIE. The relationship between multiple chronic placental lesions and HIE outcomes deserves further study.

Mitochondrial dysfunction in perinatal asphyxia: role in pathogenesis and potential therapeutic interventions.

Perinatal asphyxia (PA)-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and long-term sequelae such as spastic motor deficits, intellectual disability, seizure disorders and learning disabilities. The brain injury is secondary to both the hypoxic-ischemic event and oxygenation-reperfusion following resuscitation. Following PA, a time-dependent progression of neuronal insult takes place in terms of transition of cell death from necrosis to apoptosis. This transition is the result of time-dependent progression of pathomechanisms which involve excitotoxicity, oxidative stress, and ultimately mitochondrial dysfunction in developing brain. More precisely mitochondrial respiration is suppressed and calcium signalling is dysregulated. Consequently, Bax-dependent mitochondrial permeabilization occurs leading to release of cytochrome c and activation of caspases leading to transition of cell death in developing brain. The therapeutic window lies within this transition process. At present, therapeutic hypothermia (TH) is the only clinical treatment available for treating moderate as well as severe asphyxia in new-born as it attenuates secondary loss of high-energy phosphates (ATP) (Solevåg et al. in Free Radic Biol Med 142:113-122, 2019; Gunn et al. in Pediatr Res 81:202-209, 2017), improving both short- and long-term outcomes. Mitoprotective therapies can offer a new avenue of intervention alone or in combination with therapeutic hypothermia for babies with birth asphyxia. This review will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after PA, as a means of identifying new avenues of therapeutic intervention.

Ischemic hypoxic encephalopathy: The role of MRI of neonatal injury and medico-legal implication.

Hypoxic ischemic encephalopathy is one of the major causes of neonatal death and neurological disability in the child, and represents the most common birth injury claim. Intrapartum asphyxia often leads to several long-term sequalae, such as cerebral palsy and/or developmental delay, epilepsy. Through the neuroimaging it's possible to identify and define the different lesioned pictures and provide useful elements to establish the moment in which the damage occurred; indeed, timing of injury is a key element in the legal arena. Magnetic resonance imaging (MRI) is emerging as one of the most important tools in identifying the etiologic of neonatal encephalopathy as well as in predicting long-term outcomes. The aim of this study is to evaluate all MRI tests performed in a group of infants and young patients with possible neonatal encephalopathy, in order to determine the role of MRI in perinatal hypoxic-ischemic damage and the specific patterns that can point towards a diagnosis of the time of the damage's onset. Another goal is to assess the role of MRI in cases subject to legal-medical ligation. Since the advent of hypothermic neuroprotection, new malpractice allegations have arisen, including the failure to initiate cooling in a timely manner. In all cases, documentation of the status of the baby at birth, including a thorough neurologic exam, can be extremely helpful to the later defence of a malpractice claim, which might occur years later.

The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = -17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.

Overexpression of long non-coding RNA H19 relieves hypoxia-induced injury by down-regulating microRNA-107 in neural stem cells.

BACKGROUND: Neonatal hypoxia-ischemia (HI) is one of the commonest conditions which seriously influences the development of infants' nervous system and causes series of neurological sequelaes. The aim of the present study was to analyze the potential regulatory mechanism of long non-coding (lnc) RNA H19 under hypoxia conditions. METHODS: Neural stem cells (NSCs) were incubated in hypoxic conditions for 8 h to induce hypoxia injury. qRT-PCR was performed to detect H19 or micro (miR)-107 expression. Cell Counting Kit-8 (CCK-8) assay and Annexin V-FITC/PI staining assay were employed to detect the effects of hypoxia on cell viability and apoptosis, respectively. Moreover, NSCs were transfected with H19 overexpressing plasmid or shRNA-H19 and then subjected to hypoxia treatment. The effects of H19/miR-107 on NSC cell biological behaviors were confirmed. Furthermore, the signaling pathways involved in HI were analyzed using western blot. RESULTS: Hypoxia treatment restrained cell viability and induced cell apoptosis in NSCs. Overexpression of lncRNA H19 attenuated hypoxia-induced NSCs injury, while knockdown of lncRNA H19 aggravated NSCs injury. Further experiments suggested that miR-107 up-regulation reversed the effects of lncRNA H19 overexpression on NSCs. Moreover, the activation of Wnt/ß-catenin and PI3K/AKT pathways triggered by H19 were reversed by miR-107 up-regulation in hypoxia-treated NSCs. CONCLUSION: LncRNA H19 overexpression attenuated hypoxia-induced NSCs injury and promoted activation of Wnt/ß-catenin and PI3K/AKT pathways through downregulating miR-107.

Neonatal mortality and its associated factors among neonates admitted at public hospitals, pastoral region, Ethiopia: A health facility based study.

BACKGROUND: Neonatal mortality is a public health issue in, Ethiopia. Unfortunately, the issue is noticeably under-reported and underestimated, so the true gravity of the situation cannot be acknowledged in developing regions of the country. Regrettably, there is no single study to show the rates and predictors of neonatal mortality for Afar region. Thus, this study aims to assess neonatal mortality and associated factors in Afar region, Ethiopia. METHODS: A health facility-based cross-sectional study was conducted on 403 neonates admitted to the neonatal intensive care units (NICUs) from January 2015 to December 2019. Maternal and neonatal medical records were reviewed and audited using structured data extraction checklist. The data was collected by four trained nurses and midwives. The medical records were selected using a systematic random sampling technique. Bivariate and multivariable logistic regression analyses were done. Adjusted odds ratio with the corresponding 95% confidence interval were used to assess the association between neonatal mortality and the associated factors. Finally, the statistical significance level was declared at a p-value of less than 0.05. RESULTS: In this study, 391 medical records of newborns were included with the data complete rate of 97.02%. The prevalence of neonatal mortality was 57 (14.6%) [95% CI 11.0%-18.4%]. A multivariable logistic regression showed that lack of antenatal care (ANC) follow up [AOR = 4.69: 95%CI (1.77, 12.47)], giving birth through cesarean section [AOR 3.59, 95%CI (1.22, 10.55)], having admission temperature less than 36.5°C [AOR 10.75, 95%CI (3.75, 30.80)], birth asphyxia [AOR 7.16, 95%CI (2.22, 23.10)], and having a length of stay greater than five days in the hospital [AOR 0.23, 95%CI (0.08, 0.66)] were significantly associated with neonatal mortality. CONCLUSION: This study revealed that the rate of neonatal mortality is still high compared to the national data. Antenatal care, cesarean section delivery, length of stay in the hospital, low temperature at admission and birth asphyxia were factors associated with neonatal mortality. Thus, the health facilities should give due attention to improve antenatal care, intrapartum care and standardized care for admitted neonates. Furthermore, prospective studies are recommended.

Preclinical neurorehabilitation with environmental enrichment confers cognitive and histological benefits in a model of pediatric asphyxial cardiac arrest.

Pediatric asphyxial cardiac arrest (ACA) often leaves children with physical, cognitive, and emotional disabilities that affect overall quality of life, yet rehabilitation is neither routinely nor systematically provided. Environmental enrichment (EE) is considered a preclinical model of neurorehabilitation and thus we sought to investigate its efficacy in our established model of pediatric ACA. Male Sprague-Dawley rat pups (post-natal day 16-18) were randomly assigned to ACA (9.5 min) or Sham injury. After resuscitation, the rats were assigned to 21 days of EE or standard (STD) housing during which time motor, cognitive, and anxiety-like (i.e., affective) outcomes were assessed. Hippocampal CA1 cells were quantified on post-operative day-22. Both ACA + STD and ACA + EE performed worse on beam-balance vs. Sham controls (p < 0.05) and did not differ from one another overall (p > 0.05); however, a single day analysis on the last day of testing revealed that the ACA + EE group performed better than the ACA + STD group (p < 0.05) and did not differ from the Sham controls (p > 0.05). Both Sham groups performed better than ACA + STD (p < 0.05) but did not differ from ACA + EE (p > 0.05) in the open field test. Spatial learning and declarative memory were improved and CA1 neuronal loss was attenuated in the ACA + EE vs. ACA + STD group (p < 0.05). Collectively, the data suggest that providing rehabilitation after pediatric ACA can reduce histopathology and improve motor and cognitive ability.

Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia.

Perinatal Asphyxia (PA) is a leading cause of motor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from human adipose mesenchymal stem cells (MSC-S), preconditioned with either deferoxamine (an hypoxia-mimetic) or TNF-α+IFN-γ (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 °C for 21 min. Thereafter, 16 µL of MSC-S (containing 6 µg of protein derived from 2 × 105 preconditioned-MSC), or vehicle, were intranasally administered 2 h after birth to asphyxia-exposed and control rats, evaluated at postnatal day (P) 7. Alternatively, pups received a dose of either preconditioned MSC-S or vehicle, both at 2 h and P7, and were evaluated at P14, P30, and P60. The preconditioned MSC-S treatment (i) reversed asphyxia-induced oxidative stress in the hippocampus (oxidized/reduced glutathione); (ii) increased antioxidative Nuclear Erythroid 2-Related Factor 2 (NRF2) translocation; (iii) increased NQO1 antioxidant protein; (iv) reduced neuroinflammation (decreasing nuclearNF-κB/p65 levels and microglial reactivity); (v) decreased cleaved-caspase-3 cell-death; (vi) improved righting reflex, negative geotaxis, cliff aversion, locomotor activity, anxiety, motor coordination, and recognition memory. Overall, the study demonstrates that intranasal administration of preconditioned MSC-S is a novel therapeutic strategy that prevents the long-term effects of perinatal asphyxia.

Animal models for neonatal brain injury induced by hypoxic ischemic conditions in rodents.

Neonatal hypoxia-ischemia and resulting encephalopathies are of significant concern. Intrapartum asphyxia is a leading cause of neonatal death globally. Among surviving infants, there remains a high incidence of hypoxic-ischemic encephalopathy due to neonatal hypoxic-ischemic brain injury, manifesting as mild conditions including attention deficit hyperactivity disorder, and debilitating disorders such as cerebral palsy. Various animal models of neonatal hypoxic brain injury have been implemented to explore cellular and molecular mechanisms, assess the potential of novel therapeutic strategies, and characterize the functional and behavioural correlates of injury. Each of the animal models has individual advantages and limitations. The present review looks at several widely-used and alternative rodent models of neonatal hypoxia and hypoxia-ischemia; it highlights their strengths and limitations, and their potential for continued and improved use.